Methemoglobinemia in Emergency Medicine
- Author: David C Lee, MD; Chief Editor: Asim Tarabar, MD more...
Background
Red blood cells contain 4 hemoglobin chains. Each hemoglobin molecule is composed of 4 polypeptide chains associated with 4 heme groups. The heme group contains an iron molecule in the reduced or ferrous form (Fe2+). In this form, iron can combine with oxygen, by sharing an electron, to form oxyhemoglobin. When oxyhemoglobin releases oxygen to the tissues, the iron molecule is restored to its original ferrous state. Hemoglobin can accept and transport oxygen only when the iron atom is in its ferrous form. When hemoglobin loses an electron and becomes oxidized, it is converted to the ferric state (Fe3+) or methemoglobin. Methemoglobin lacks the electron that is needed to form a bond with oxygen and, thus, is incapable of oxygen transport. Because red blood cells are continuously exposed to various oxidant stresses, blood normally contains approximately 1% methemoglobin levels.
This low level of methemoglobin is maintained by 2 important mechanisms. One protective mechanism against oxidizing agents is the hexose-monophosphate shunt pathway within the erythrocyte. Through this pathway, oxidizing agents are reduced by glutathione prior to the formation of methemoglobin. The second and more important mechanism against methemoglobin formation uses 2 enzyme systems, diaphorase I and diaphorase II.
These 2 enzyme systems require nicotinamide adenine dinucleotide (NADH) and nicotinamide adenine dinucleotide phosphate (NADPH), respectively, to reduce methemoglobin to its original ferrous state. Diaphorase II quantitatively contributes only a small percentage of the red blood cells reducing capacity. However, diaphorase II can be pharmacologically activated by exogenous cofactors (ie, methylene blue) to 5 times its normal level of activity. Traditionally, methemoglobinemia is considered an acquired disorder; however, a very small number of congenital cases are also reported in the literature.
Pathophysiology
Oxidation of iron to the ferric state reduces the oxygen-carrying capacity of hemoglobin and produces a functional anemia. In addition, a ferric heme group affects nearby ferrous heme groups. Ferric heme groups impair the release of oxygen from nearby ferrous heme groups on the same hemoglobin tetramer. The result of methemoglobinemia is that oxygen delivery to tissues is impaired and the oxygen hemoglobin dissociation curve shifts to the left.
Organs with high oxygen demands (ie, CNS, cardiovascular system) usually are the first systems to manifest toxicity. Oxygenated blood is red, deoxygenated blood is blue, and blood-containing methemoglobin is a dark reddish brown color. This dark hue imparts clinical cyanosis when methemoglobin levels are at 1.5 g/dL (approximately 10-15% methemoglobin concentration); however, a level of 5 g/dL of deoxygenated blood is required for similar effects. Therefore, when methemoglobin levels are relatively low, cyanosis may be observed without cardiopulmonary symptoms.
Varying concentrations of methemoglobin are shown in the image below.
Note the chocolate brown color of methemoglobinemia. Tube 1 and tube 2 have a methemoglobin concentration of 70%; tube 3, a concentration of 20%; and tube 4, a normal concentration. Epidemiology
Mortality/Morbidity
As methemoglobin levels increase, patients demonstrate evidence of cellular hypoxia. Death occurs when methemoglobin fractions approach 70%. Death can occur at lower levels in patients with significant comorbidities.
Race
The color change of the skin may be harder to detect in patients with darker skin color.
Age
Children, especially those younger than 4 months, are particularly susceptible to methemoglobinemia.
The primary erythrocyte protective mechanism against oxidative stress is the NADH system. In infants, this system has not fully matured, and the NADH methemoglobin reductase activity and concentrations are low.
Moore TJ, Walsh CS, Cohen MR. Reported adverse event cases of methemoglobinemia associated with benzocaine products. Arch Intern Med. Jun 14 2004;164(11):1192-6. [Medline].
Ash-Bernal R, Wise R, Wright SM. Acquired methemoglobinemia: a retrospective series of 138 cases at 2 teaching hospitals. Medicine (Baltimore). Sep 2004;83(5):265-73. [Medline].
US Food and Drug Administration. FDA Drug Safety Communication: Serious CNS reactions possible when methylene blue is given to patients taking certain psychiatric medications. Available at http://www.fda.gov/Drugs/DrugSafety/ucm263190.htm. Accessed July 27, 2011.
Conkling PR. Brown blood: understanding methemoglobinemia. N C Med J. Mar 1986;47(3):109-11. [Medline].
Ellenhorn MJ, Barceloux DG. Nitrates, nitrites, and methemoglobinemia. In: Medical Toxicology, Diagnosis and Treatment of Human Poisonings. 1988:844-851.
Fitzsimons MG, Gaudette RR, Hurford WE. Critical rebound methemoglobinemia after methylene blue treatment: case report. Pharmacotherapy. Apr 2004;24(4):538-40. [Medline].
Henretig FM, Gribetz B, Kearney T, Lacouture P, Lovejoy FH. Interpretation of color change in blood with varying degree of methemoglobinemia. J Toxicol Clin Toxicol. 1988;26(5-6):293-301. [Medline].
Herman MI, Chyka PA, Butler AY, Rieger SE. Methylene blue by intraosseous infusion for methemoglobinemia. Ann Emerg Med. Jan 1999;33(1):111-3. [Medline].
Howland MA. Methylene blue. In: Goldfrank's Toxicologic Emergencies. 8th ed. 2006:1746-1748.
Price D. Methemoglobin inducers. In: Goldfrank's Toxicologic Emergencies. 8th ed. 2006:1734-1745.
Umbreit J. Methemoglobin--it's not just blue: a concise review. Am J Hematol. Feb 2007;82(2):134-44. [Medline].
Print
